Determining cell-specific mechanisms that drive aberrant bone regeneration in Down syndrome

确定驱动唐氏综合症骨再生异常的细胞特异性机制

• 批准号: 10654983
• 负责人: Lindsay A Dawson
• 金额: $ 163.35万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654983
• 关键词: Acute; Age; Aging; Amputation; Anabolic Agents; Antibodies; Bone Density; Bone Injury; Bone Regeneration; Bone Resorption; Cells; Chromosome 21; Complex; Craniofacial Abnormalities; Databases; Defect; Digit structure; Down Syndrome; Encapsulated; Environment; Exhibits; Female; Foundations; Gene Expression; Goals; Human; Human Chromosomes; Impairment; Inbred ICR Mice; Individual; Injury; Life Expectancy; Live Birth; Metabolic; Modeling; Molecular; Mus; Osteoblasts; Osteoclasts; Osteoporosis; Outcome; Patients; Phalanx; Phase; Phenotype; Population; Populations at Risk; Process; Proliferating; Research; Resolution; Testing; Translating; Trisomy; Vulnerable Populations; age effect; age related; aged; bone; bone cell; bone fracture repair; bone healing; bone mass; bone strength; bone turnover; cell type; early onset; healing; in vivo; male; mouse Ts65Dn; mouse model; normal aging; recruit; response; response to injury; sex; sexual dimorphism; skeletal; skeletal injury; skeletal regeneration; stem cells; therapy development; transcriptome; young adult

PROJECT SUMMARY This new R01 application entitled “Determining cell-specific mechanisms that drive aberrant bone regeneration in Down syndrome” is focused on identifying the mechanistic and cellular changes that drive age-and-sex-specific deficits in skeletal regeneration as well as rescuing bone regeneration using multiple murine models of Down syndrome (DS). All individuals with DS exhibit hallmark skeletal defects, i.e. short stature and craniofacial abnormalities, and collectively present with a sexually dimorphic and variable spectrum of low bone mineral density (BMD) that predisposes this vulnerable group to skeletal injuries. Remarkably, male DS patients display an earlier onset and greater propensity for low BMD than DS females. Recent studies using murine models of DS (Dp16 and Ts65Dn mice) to parallel both the variability and the sexually dimorphic low BMD observed in DS patients, have shown that fracture healing is severely impaired in male DS mice and female Dp16 mice, whereas Ts65Dn females heal fractures at a similar rate as wild-type controls. These findings demonstrate how low BMD in DS mice translates to an injury environment that if recapitulated in humans would have profound consequences for this at-risk group, especially as they age. To understand the complex bone healing phenotype in DS, this project utilizes a mammalian model of bone regeneration, amputation of the digit tip, the terminal phalanx (P3), as well as multiple DS murine models (Dp16 and Ts65Dn mice) that possess inherently different mechanisms of bone accrual that recapitulate the sexually dimorphic low BMD phenotype observed in DS patients. Studies in Aim 1 will establish an expansive and high resolution DS transcriptome database in the context of an acute P3 bone injury response, as well as characterize osteoclast and osteoblast recruitment and activity during bone regeneration in multiple murine models of DS. Studies in Aim 2 will decouple the sexually dimorphic DS-related impacts from the sexually dimorphic aged-related impacts on osteoclasts and osteoblasts in the setting of bone regeneration. Aim 3 will determine the capacity for bone anabolic agents (PTH and anti-sclerostin antibody) to rescue bone regeneration in DS mice. The successful completion of this project will provide the foundation for developing fine-tuned sex-and-age-specific therapies to mitigate the consequences of poor bone healing in DS individuals.

项目摘要 这种新的R01应用名为“确定驱动降低异常骨再生的细胞特异性机制 综合征”的重点是识别驱动年龄特异性定义的机械和细胞变化 使用多个唐氏综合症（DS）的多种鼠模型来挽救骨再生。所有人 具有DS暴露的Hallmark骨骼缺陷，即身材矮小和颅面异常，并共同出现 低骨矿物质密度（BMD）的性二态和可变光谱，使这一脆弱的群体容易 骨骼损伤。值得注意的是，男性DS患者的BMD比DS表现出更早的发病和更高的可靠性 女性。最近使用DS（DP16和TS65DN小鼠）的鼠模型的研究与可变性平行 在DS患者中观察到的二态低BMD，表明雄性DS小鼠的骨折愈合严重受损 雌性DP16小鼠，而TS65DN雌性以与野生型对照相似的速率治疗骨折。这些发现 证明DS小鼠中BMD低的BMD转化为损伤环境，如果在人类中概括， 对这个高危人群的深刻影响，尤其是随着年龄的增长。了解复杂的骨骼愈合表型 DS，该项目利用骨骼再生的哺乳动物模型，数字尖端的截肢，末端Phalanx（P3），作为 以及多种DS鼠模型（DP16和TS65DN小鼠），具有固有不同机制 这概括了DS患者观察到的性二态低BMD表型。 AIM 1的研究将建立 在急性P3骨损伤反应的背景下，膨胀和高分辨率DS转录组数据库以及 在多个鼠模型中，骨骼再生过程中的破骨细胞和成骨细胞募集和活性。 AIM 2中的研究将使性二态DS相关的性影响与性二态性老年相关的影响相结合 在骨再生环境中的破骨细胞和成骨细胞上。 AIM 3将确定骨合成代谢剂的能力 （PTH和抗骨蛋白抗体）挽救DS小鼠的骨再生。这个项目的成功完成将 为开发微调的性和年龄特异性疗法提供基础，以减轻骨头的后果 DS个人的康复。